The purpose of this project is to find genes that impair cortical function and, in doing so, increase the risk for developing Schizophrenia. The methods to be used include family based and case control comparisons. Abnormalities of cortical function appear to be core features of chronic Schizophrenia. Cortical function of patients and their siblings will be quantified using functional Magnetic Resonance Imaging (fMRI), Magnetic Resonance Spectroscopy and neuropsychological testing. Results using these methods will be combined with genetic data to look for genes that affect brain function and increase susceptibility to Schizophrenia. Carefully diagnosed patients will be recruited from local and national sources. Diagnosis of probands is established from previous psychiatric records and a structured diagnostic interview. Siblings and control subjects likewise are evaluated with a structured interview. All subjects give a blood sample for genetic analysis. Evaluation of cortical function is performed using fMRI and neuropsychological testing. These procedures have been chosen because patients with Schizophrenia demonstrate some abnormality compared to normal controls. We have recently shown that subsets of their healthy siblings show one or more abnormal traits on these tests, suggesting these measures may be useful measures for detecting genes that increase risk for schizophrenia. Another study used imaging genetics to examine the contribution of causative variants and haplotypes to the risk of schizophrenia. This is essential for complex genetic disorders where multiple functional sites are implicated within a single gene. With this method, complex genetic variation can be validated functionally in humans and linked to prefrontal inefficiency. These studies and the methods used are unique in focusing on such biological variables. We anticipate that this will increase the statistical power to find schizophrenia genes. Our initial results have been very promising. We have found evidence that four genes affect cortical processing. Two of these genes also increase risk for developing schizophrenia. First, a gene on chromosome 22, called COMT, is important in regulating prefrontal dopamine metabolism and cognitive processes subserved by the prefrontal cortex. These cognitive processes, generically referred to as working memory and executive function, are impaired in patients with schizophrenia. We have shown in this study that a variant of the COMT gene impairs working memory and executive function and, in doing so, slightly increases risk for developing schizophrenia. Second, we have recently replicated findings of other researchers by showing that a gene on chromosome 6, called dysbindin, increases risk for schizophrenia. We have extended these findings by showing that this gene may exert its effects by slowing processing time and slightly reducing IQ. Third, a gene called BDNF, known to be critically involved in memory in many other animal species, has a recent human mutation (called val66met). Our results show this mutation impairs cortical function and memory by changing how the protein is processed. This memory gene may have deleterious effects in other illnesses where memory is impaired. Finally, a gene that increases risk for depression and anxiety, the serotonin transporter, may exert its effects by over-activating cortical regions responsible for processing information related to fear. More recent data has implicated 7 additional genes. These include DISC1, G72, neuregulin, GRM3, MRDS1, and GAD1. The first three of these have previously been implicated in schizophrenia by other groups following up linkage studies. We have found additional supportive evidence that these genes increase risk for schizophrenia and/or cognitive deficits typically found in schizophrenia. For example, DISC1, which is highly expressed in hippocampus, appears to have subtle deleterious effects on long term memory in patients as well as hippocampal physiological responses. GRM3, which regulates synaptic glutamate, has similar deleterious effects on both hippocampal and prefrontal physiological responses and related cognitive processes. An examination of the relationship between selected cognitive measures and a set of G72 SNPs showed that cognitive measure become progressively more compromised with increased risk allele load, suggesting that a mutation in G72 may be particularly penetrant at the level of brain information processing implicated in cognitive impairment. In a recent study found that subjects with a genotype associated with an increased risk for schizophrenia had lower levels of the neurochemical (NAA) which is indicative of decreased neuronal function and loss. These data are further evidence that glutamate system dysfunction may play a role in the prefrontal functional abnormalities seen in schizophrenia. Furthermore, evidence that it increases risk for schizophrenia was detected in three separate cohorts. Our most recent findings indicate that polymorphisms of the COMT gene may also alter the effects of drugs, which specifically target the dopaminergic system, on the prefrontal cortex. These compounds have the ability to regulate dopaminergic transmission in the synaptic terminals without affecting the neurotransmission on subcortical systems in addition to improving cognitive function by increasing dopamine load. This study provides an example of:1) targeted pharmacology for the treatment of cognitive deficits in schizophrenia in which the dorsolateral prefrontal cortex is compromised and 2) the effect of these drugs may be modified by interactions with the COMT genotype illustrating that this new pharmacological approach may be genotyped-based. The results of these studies are notable for three reasons. First, they begin to put together some of the pieces in the very complex disorder of schizophrenia and suggest potential new treatments, such as COMT inhibitors. Second, they show how this combination of clinical, physiological, and molecular techniques can produce compelling, convergent results showing how genes affect brain physiology and risk for mental illness. Finally, they offer a new opportunity to study, in animal models, how various combinations of these deleterious genes can impact downstream molecular processes that might mediate their psychogenic effects.